遺伝子プロファイリングによりACE阻害薬治療の有益性が上昇する

EUROPA:遺伝子プロファイリングモデルによりACE阻害薬の治療による有益性が予測され推奨される治療の効果が最大限になる
EUROPA: Genetic profiling model predicts treatment benefits of ACE inhibitors and optimizes recommended therapy
2010年European Society of Cardiology学会で発表された研究により、ACE阻害薬治療の有益性を予測し推奨された治療の効果を最大限にするある遺伝子プロファイリングが同定された。約9.000人の安定したCAD患者が選択され、EUROPAとして知られる無作為化プラセボコントロールトライアルに参加した。研究者らは、ACE阻害薬の薬力学的パスウェイ内に存在することが確認されている12の候補遺伝子を52のハプロタイプタギング一塩基多型(SNPs)を用いて解析した。主要アウトカムは4年間の追跡期間中の心血管死亡、非致死性心筋梗塞、蘇生された心停止の減少であった。交絡因子で多変量調節し複数の検査で修正した結果、アンジオテンシンIIタイプI受容体遺伝子およびブラジキニンタイプI受容体遺伝子に位置する3つのSNPsがペリンドプリル治療の有益性と有意に関連があった。薬理遺伝学的スコアとこれら3つのSNPsを組み合わせると、スコア上昇に伴いプラセボ群において段階的なリスクの低下が認められペリンドプリル群では段階的な治療有益性の低下が認められた。73.5%のサブグループの患者においては治療の有益性が著明に認められたが、残りの26.5%においては明らかな有益性は認められなかった。
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A research program presented during the European Society of Cardiology Congress 2010 identified a genetic profiling model that predicts the treatment benefits of ACE inhibitors and optimizes the recommended therapy.

The advantages of prescribing angiotensin-converting enzyme (ACE) inhibitors for stable coronary artery disease (CAD) may be increased by targeting the therapy to the patients most likely to benefit. Clinical characteristics alone do not allow a reliable identification of these patients, so a research program was carried out at Erasmus University Medical Centre in Rotterdam to develop a genetic profiling model that predicts the treatment benefits of ACE inhibitors and optimizes the recommended therapy.

Research lead, Doctor Jasper Brugts, explained the methodology used, "Around 9,000 stable CAD patients were selected to take part in a randomized, placebo-controlled trial known as EUROPA. We analyzed 12 candidate genes that were determined as being within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging single nucleotide polymorphisms (SNPs). The primary outcome was a reduction in cardiovascular mortality, non-fatal myocardial infarction and resuscitated cardiac arrest over a four-year follow-up period."

Three SNPs, located in the angiotensin-II type I receptor genes and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing score.

A pronounced treatment benefit was observed in a subgroup of 73.5 percent of the patients, while no benefit was apparent in the remaining 26.5 percent. An interaction effect of similar direction and magnitude, although not statistically significant, was observed in a preliminary confirmatory analysis of over 1,000 patients with cerebrovascular disease, who were treated with perindopril or placebo from the PROGRESS-trial.

This research study is the first to identify genetic determinants of the treatment benefit of ACE-inhibitor therapy. A group of responders (73.5 percent) and non-responders (26.5 percent) to treatment was identified by genetic markers. If confirmed in subsequent studies, these findings open the route to individualize therapy by pharmacogenetic profiling. Such individualized therapy could revolutionize medical drug therapy by prescribing drugs only to those patients most likely to benefit from the therapy. This would not only increase efficacy, but also decrease unnecessary treatment of patients and avoid unwanted side effects, thereby decreasing the overall costs.